Mycobacterium avium complex

• Mycobacterium avium complex (MAC) is a group of environmental, slow-growing, non-tuberculous mycobacteria found in water, soil and household dust. Infection comes from inhaling or swallowing the organism, not from another person.
• In advanced HIV with a CD4 count under 50 cells per microlitre, MAC usually causes disseminated disease: fever, night sweats, weight loss, diarrhoea, abdominal pain, anaemia and hepatosplenomegaly. Acid-fast blood cultures make the diagnosis. ^[3]
• In people without advanced immunosuppression, pulmonary MAC occurs mainly in older women (often thin, with bronchiectasis and a chronic cough they suppress) and in men with chronic lung disease and smoking damage.
• Treatment is a macrolide plus ethambutol, with or without a rifamycin (rifabutin), for at least 12 months and until the CD4 count is above 100 cells per microlitre for 6 months and symptoms have resolved; effective antiretroviral therapy (ART) is started or continued.
• Routine primary prophylaxis against MAC is no longer recommended when ART is started promptly and the viral load is suppressed; it is reserved for people with a CD4 count under 50 who are not on effective ART. ^[3]
• Low-resource settings face a special problem: MAC and tuberculosis look alike, acid-fast smears cannot tell them apart, and mycobacterial culture is often unavailable. ^[4]

By the end of this page you should be able to:

1. Explain where MAC comes from and how it differs from tuberculosis.
2. Recognise disseminated MAC in a person with advanced HIV and know what tests to request.
3. Recognise pulmonary MAC in an older woman with bronchiectasis and in a man with COPD.
4. Choose and monitor a macrolide-based, three-drug regimen and say when it can be stopped.
5. Manage the interaction between rifamycins and antiretroviral therapy.
6. State the current indications for (and against) primary and secondary prophylaxis.
7. Plan a diagnostic and treatment approach in a low-resource setting.

MAC behaves clinically as two different problems and the management is different for each:

• Disseminated MAC is a disease of immunosuppression. It is an AIDS-defining condition and is also seen in other severely immunosuppressed patients, such as those after transplantation.
• Pulmonary MAC is a disease of damaged airways. It can occur in immunocompetent people with underlying structural lung disease, and it is generally not disseminated.

Other MAC syndromes, less common, include cervical lymphadenitis in children, soft tissue and musculoskeletal infection, and catheter-associated disease. This page covers the disseminated and pulmonary forms in detail, because these are the ones a clinician is most likely to treat.

MAC is found worldwide in the environment. In the United States the reported prevalence of disease caused by MAC ranges from about 1.4 to 6.6 per 100,000 people, with no recognised endemic area, and infection is increasing in many regions. Women have a higher overall prevalence than men (up to about 1.6-fold), driven by the nodular bronchiectatic pulmonary form. One Australian study found a higher prevalence in men, probably because of differences in the type of disease measured rather than a true contradiction. ^[1]

In the era before effective ART, disseminated MAC developed in 20% to 40% of people with advanced HIV and a CD4 count under 50 cells per microlitre, and MAC was the most frequent bacterial opportunistic infection in AIDS. With widespread ART the incidence has fallen dramatically. Even so, disseminated MAC is still found in people who present late, who are not taking ART, or whose virus is not suppressed. ^[6]

Pulmonary MAC is increasing in older adults, especially in settings where computed tomography detects bronchiectasis and small nodules. It is less common in men in most series and much more common in men with chronic lung disease.

Regional note: MAC is rare in low- and middle-income countries compared with the United States and Europe. Studies from Uganda, Cote d'Ivoire and several South American and African centres found MAC in only a small minority of patients with advanced AIDS and chronic diarrhoea, even when tuberculosis was common. This matters for both diagnosis and for how much prophylaxis is justified.

The decisive risk factor is immunosuppression. Disseminated disease is most common when:

• the CD4 count is under 50 cells per microlitre in a person with HIV;
• the person is not on effective ART or remains viremic despite treatment;
• there are no options for a fully suppressive ART regimen.

In the pre-ART era, MAC that disseminated was almost always Mycobacterium avium (more than 95% of cases in advanced HIV). For reasons that are not well understood, Mycobacterium intracellulare rarely disseminates in HIV. ^[3][6]

Other settings include inherited or acquired defects of interferon-gamma signalling, lymphoreticular malignancy with low CD4 counts, and profound immunosuppression after transplantation.

The organism exploits damaged or poorly cleared airways. Recognised risk factors include:

• chronic obstructive pulmonary disease and other chronic lung diseases;
• bronchiectasis;
• cystic fibrosis;
• pneumoconiosis and industrial lung exposure;
• thoracic and skeletal abnormalities such as severe scoliosis and straight back syndrome;
• mitral valve prolapse;
• older age;
• being an older woman who suppresses her cough (the nodular bronchiectatic form, historically called Lady Windermere syndrome);
• immunosuppression, including after transplantation and in AIDS;
• family clustering (siblings of an index patient have a much higher prevalence than the general population).

No modifiable risk factor for sporadic MAC has been established in otherwise healthy people. Female sex is associated with the nodular bronchiectatic form; fibrocavitary disease is more common in men with pre-existing structural lung disease.

MAC is acquired from the environment by inhalation or by ingestion into the gastrointestinal tract. In the lung it adheres to mucosal epithelial cells, is taken up by macrophages, spreads through local lymphatics to lymph nodes and then, if immunity fails, disseminates throughout the body via the bloodstream and lymphatics. The organisms grow slowly (colonies take about 10 to 20 days to mature) and resist drying and low temperatures, which is why they persist in hot water systems, bathrooms and household dust. ^[1]

What happens next depends entirely on the host:

• In a healthy person with working alveolar macrophages and T-cell immunity, inhaled organisms are cleared or kept latent. Most exposures cause no disease.
• In a person with damaged airways (COPD, bronchiectasis) the organism is not cleared from damaged segments. It colonises bronchiectatic segments, provokes inflammation and slowly worsens bronchiectasis, forming a cycle of damage.
• In advanced immunosuppression, macrophages cannot contain the organism. It replicates in macrophages, spreads to bone marrow, liver, spleen and lymph nodes, and produces the systemic syndrome. It can also cause anaemia by suppressing erythropoiesis.

There is no person-to-person transmission, so infection control precautions are not required for patients.

MAC is a non-motile, non-spore-forming, gram-positive, acid-fast bacillus. It is a non-chromogen in Runyon group III. It is slow-growing, and Mycobacterium avium grows best at about 34.5 degrees C, while Mycobacterium intracellulare grows best at 31.5 degrees C; both grow between 28 and 38.5 degrees C. ^[1]

Because the species look identical on staining and culture, distinguishing them requires molecular methods (polymerase chain reaction, restriction fragment length polymorphism or multilocus sequence typing). For clinical care the distinction matters most in HIV, where Mycobacterium avium dominates and Mycobacterium intracellulare rarely disseminates.

On biochemical testing MAC is catalase-positive and negative for niacin, nitrate reduction and tween hydrolysis, but these are inadequate for clinical use; molecular testing is preferred.

Susceptibility testing has a limited but important role. There is no proven correlation between in-vitro susceptibility and clinical response for most drugs. Testing for macrolide susceptibility (clarithromycin or azithromycin) and amikacin susceptibility is useful, and for refractory or severe disease testing secondary drugs is reasonable.

Symptoms are non-specific and can start weeks before cultures become positive. The common findings are ^[1]:

• fever (more than 80% of patients);
• night sweats (more than 35%); ^[6]
• weight loss (more than 25%); ^[6]
• abdominal pain and diarrhoea;
• mesenteric and generalised lymphadenopathy;
• anaemia (often marked);
• elevated alkaline phosphatase and lactate dehydrogenase;
• hepatosplenomegaly.

Other findings include severe wasting, synovitis and tenosynovitis. In children the presentation is different: MAC more often causes cervical lymphadenitis, which usually runs a benign course, sometimes with rupture of nodes and sinus tract formation. Localised forms (osteomyelitis, cutaneous lesions) have been described outside advanced HIV.

Pulmonary disease has two main radiologic patterns, and they map to different people:

• Nodular bronchiectatic form: smaller than 5 mm to 10 mm nodules closely associated with areas of bronchiectasis, with a predilection for the middle lobe and the lingula. This is more common in older Caucasian women who suppress their cough. Computed tomography is far more sensitive than chest radiography for showing bronchiectasis, small nodules, tree-in-bud appearances, ground-glass opacities and pleural thickening. ^[1]
• Fibrocavitary form: thin-walled cavities with a predilection for the upper lobes, with tree-in-bud opacities suggesting endobronchial spread. This is more common in Caucasian men with underlying chronic lung disease and causes cough, haemoptysis and constitutional symptoms.

Symptoms in immunocompetent patients are non-specific, with chronic cough the most frequent. Fever, weight loss and haemoptysis are less common than in tuberculosis and are uncommon in patients with HIV. Pleural involvement occurs in 5% to 15% of patients. The differential of pulmonary MAC is wide: tuberculosis, fungal infection, hypersensitivity pneumonitis, sarcoidosis, and lung cancer. ^[1]

The organism is most often found incidentally or during investigation of chronic cough, haemoptysis, or bronchiectasis, and it should not be assumed to be harmless: more than one positive culture in a symptomatic patient with compatible imaging is clinically significant.

The clinical problems that MAC mimics:

• tuberculosis (often co-exists or is misdiagnosed);
• fungal infection and endemic mycoses;
• lymphoma and leukaemia;
• other opportunistic infections of advanced HIV (Pneumocystis pneumonia, cryptococcal disease);
• malignancy with constitutional symptoms;
• sepsis from enteric pathogens.

• tuberculosis;
• lung cancer (a single large nodule or mass);
• fungal infection;
• hypersensitivity pneumonitis;
• sarcoidosis;
• chronic suppuration from asthma and allergic bronchopulmonary aspergillosis.

A useful clinical rule: when a patient with advanced HIV is treated empirically for tuberculosis and improves only partially, or when acid-fast smears remain positive after appropriate tuberculosis therapy, MAC should be actively excluded with culture.

Per the ATS/IDSA criteria, the evaluation of suspected NTM pulmonary disease combines clinical, radiologic and microbiologic assessment ^[2]:

1. Clinical: pulmonary or systemic symptoms.
2. Radiologic: nodular or cavitary opacities on chest radiography, or high-resolution CT showing bronchiectasis with multiple small nodules, after appropriate exclusion of other diagnoses.
3. Microbiologic: positive cultures from at least two separate expectorated sputum samples collected more than a week apart; or positive culture from at least one bronchial wash or lavage; or lung biopsy showing granulomatous inflammation or acid-fast bacilli with positive culture or positive sputum or lavage culture.

Clinically significant MAC pulmonary disease is unlikely with a single positive sputum culture during initial evaluation but occurs in up to 98% of patients with two or more positive cultures of the same species. ^[2]

Supportive tests:

• High-resolution CT of the chest to define the radiologic pattern and extent.
• Basic laboratory tests and assessment of the ability to tolerate prolonged multidrug therapy, baseline renal and hepatic function, and auditory and visual criteria before starting treatment.
• Bronchoscopy with lavage when sputum is inadequate or when an alternative diagnosis is suspected.

The key test is blood culture for mycobacteria. In advanced HIV:

• Two or more sets of blood (and/or bone marrow, lymph node or tissue) cultures for mycobacteria are recommended. Bone marrow culture has a lower yield, particularly when blood cultures are negative.
• The isolation of MAC from blood, bone marrow, lymph node or other normally sterile site in a symptomatic patient confirms disseminated disease.
• Acid-fast (Ziehl-Neelsen or auramine) staining of tissue or bone marrow may show bacilli but does not distinguish MAC from Mycobacterium tuberculosis.
• Routine labs often show anaemia, elevated alkaline phosphatase and lactate dehydrogenase, hyponatraemia and low serum albumin.

For pulmonary disease the diagnosis is not made from culture alone. A patient must meet all three clinical, radiologic and microbiologic criteria ^[2]. Meeting them does not automatically mean treatment is required: the decision to treat depends on symptoms, imaging, growth of the organism, and the risks of prolonged multidrug therapy, ideally discussed with the patient.

For disseminated disease, the diagnosis rests on compatible clinical features plus isolation of MAC from a sterile site (blood, bone marrow or other tissue) ^[3].

Before starting treatment, every MAC isolate should be tested for susceptibility to clarithromycin or azithromycin. Macrolide susceptibility is a consistent predictor of treatment success for pulmonary MAC, and loss of the macrolide from the regimen is associated with markedly reduced sputum conversion and higher mortality ^[2]. For refractory disease, testing amikacin and second-line agents is useful.

The preferred initial therapy is at least two drugs ^[3]:

• Clarithromycin 500 mg by mouth twice daily plus ethambutol 15 mg/kg by mouth daily; or ^[3]
• Azithromycin 500 to 600 mg plus ethambutol 15 mg/kg daily when clarithromycin is not tolerated, cannot be used because of interactions or adherence is a problem; ^[3]

with, in severe disease, a third drug:

• Rifabutin 300 mg by mouth daily (dose adjusted for ART interactions); or a fourth drug such as a fluoroquinolone (levofloxacin 500 mg daily, or moxifloxacin 400 mg daily) or an injectable aminoglycoside (amikacin 10 to 15 mg/kg intravenously daily), the latter reserved for refractory disease. ^[3]

Use clarithromycin or azithromycin as the macrolide backbone. Azithromycin is generally preferred in patients on complex ART because it has no major cytochrome P450 interaction, whereas clarithromycin is a strong CYP3A inhibitor. Clarithromycin doses above 1 g per day are contraindicated because of an association with increased mortality in advanced HIV ^[6].

Other considerations:

• Antiretroviral therapy can begin at the same time. Rifabutin can be used instead of rifampin to avoid drug-drug interactions with antiretrovirals ^[1].
• Blood cultures should be monitored until they become negative. Symptomatic improvement often begins within a few weeks.
• Watch for drug toxicity: optic neuritis and visual acuity or colour vision change with ethambutol, uveitis with rifabutin, hearing loss with aminoglycosides, and QT prolongation with macrolides.

• People with HIV and disseminated MAC should be treated for at least 12 months ^[3], or shorter courses only when immunologic recovery on ART is strong ^[3].
• Before stopping treatment, the CD4 count should be above 100 cells per microlitre for at least 6 months and the virus suppressed, and there should be no signs or symptoms of MAC disease ^[3]. ^[7]

Evidence that supports immune-based discontinuation: in treated patients who sustained immune recovery on ART, bone marrow and blood cultures remained sterile months after stopping antimycobacterial therapy, supporting the concept that disseminated MAC can be cured when ART works ^[7].

The same drug regimen is continued as chronic maintenance (secondary prophylaxis) when immune recovery has not been achieved. It can be stopped when all of the following are met ^[3]:

• at least 12 months of therapy completed;
• no signs or symptoms of MAC disease;
• sustained (at least 6 months) CD4 count above 100 cells per microlitre on effective ART.

It should be restarted if the CD4 count stays under 100 cells per microlitre or a fully suppressive ART regimen cannot be achieved ^[3].

Not every positive culture needs treatment. The ATS/IDSA guideline suggests starting antimicrobial treatment rather than watching in patients who meet diagnostic criteria, especially with positive acid-fast smears or cavitary disease, but the decision should be individualised. Watchful waiting with clinical and radiologic review every 3 to 6 months is reasonable for patients with mild, non-progressive, nodular disease and low symptom burden ^[1][2].

For macrolide-susceptible MAC pulmonary disease the guideline recommends a three-drug regimen containing a macrolide (strong recommendation) rather than a regimen without a macrolide, and at least three drugs rather than two ^[2]. The panel suggests azithromycin-based regimens over clarithromycin, for better tolerance, fewer interactions and equal efficacy ^[2]. A standard oral regimen is:

• macrolide: azithromycin or clarithromycin at usual guideline doses;
• ethambutol 15 mg/kg by mouth daily (the dose used in disseminated MAC regimens); ^[3]
• rifampicin or rifabutin, the latter at 300 mg daily when used, to reduce drug interactions;

with parenteral amikacin or streptomycin added in the initial 2 to 3 months for cavitary or severe bronchiectatic or macrolide-resistant disease. ^[2]

Dosing frequency depends on the radiologic pattern ^[2]:

• Non-cavitary nodular or bronchiectatic disease: three times weekly therapy is suggested (intermittent regimens have similar sputum conversion, fewer side effects and no observed macrolide resistance in trials).
• Cavitary or advanced or severe non-nodular disease: daily therapy. ^[2]
• Inhaled amikacin liposome suspension is reserved for patients who have failed at least six months of guideline-based therapy ^[2].

At least 12 months after sputum culture conversion ^[2]. Sputum conversion usually takes several months, so total treatment often extends well beyond 12 months. In patients co-infected with HIV, treatment should continue until the CD4 count is above 100 cells per microlitre for at least 6 months ^[7].

Surgical resection of the diseased lung can be considered for localised, drug-resistant, or refractory disease with haemoptysis, after sputum conversion, by a surgeon experienced in mycobacterial disease ^[2].

Rifampin is a potent CYP3A4 and UGT1A1 inducer and lowers exposure of protease inhibitors by 80 to 95%, of most non-nucleoside reverse transcriptase inhibitors (except efavirenz) and of several integrase inhibitors (bictegravir, elvitegravir/cobicistat), so standard doses cannot be co-administered. Practical points: ^[6]

• Efavirenz (600 mg daily) is the ART backbone best tolerated with rifampin. ^[6]
• Dolutegravir or raltegravir can be used with rifampin if dosed twice daily (dolutegravir 50 mg twice daily, or raltegravir 800 mg twice daily). ^[6]
• Rifabutin is preferred over rifampin in patients on most ART, with little effect on integrase-based regimens.
• Clarithromycin is a CYP3A inhibitor and its levels rise with boosted protease inhibitors. With such ART, switch to azithromycin or reduce the clarithromycin dose.
• Ethambutol, azithromycin and the fluoroquinolones do not require dose adjustment for ART.

ART should be started or continued. It allows immune reconstitution and, in the long term, makes MAC treatment stoppable and improves survival. Immune reconstitution inflammatory syndrome occurs only in a minority of patients and is usually manageable. Do not stop ART because MAC is diagnosed ^[6].

Routine primary prophylaxis against MAC is not recommended in people who immediately start effective ART. Current indications ^[3]:

• Offer prophylaxis only when the CD4 count is under 50 cells per microlitre and the person is not on ART, remains viremic on ART or has no option for a fully suppressive regimen, and disseminated MAC has first been excluded with blood cultures. ^[1]
• Regimens:
  • Azithromycin 1,200 mg by mouth once weekly, or ^[3]
  • Clarithromycin 500 mg by mouth twice daily, or
  • Azithromycin 600 mg by mouth twice weekly (a less preferred alternative). ^[3]
• Alternative for those intolerant of macrolides: rifabutin 300 mg by mouth daily. ^[3]
• Primary prophylaxis is not recommended when a fully suppressive ART regimen is being started ^[3].

Historically, in the pre-ART era and in the USPHS/IDSA guidance, prophylaxis was recommended for adults and adolescents with CD4 counts under 100 cells per microlitre, most commonly with rifabutin 300 mg daily. That threshold has since been lowered to under 50 and prophylaxis is now restricted to people not virologically suppressed ^[5].

Continued treatment after a documented episode is the same as chronic maintenance therapy. Discontinue when the criteria in the management section are met. Restart if the CD4 count stays under 100 or a fully suppressive regimen is impossible ^[3].

• Severe wasting and profound anaemia (often transfusion-dependent in untreated disease).
• Hepatosplenomegaly and generalised lymphadenopathy.
• Mesenteric lymphadenopathy with abdominal pain and diarrhoea.
• Localised infection: osteomyelitis, tenosynovitis, cutaneous disease and (in young children) cervical lymphadenitis.
• Immune reconstitution inflammatory syndrome after ART, presenting with fever, lymphadenitis or worsening focal disease; usually self-limited and treated supportively.
• Drug toxicity: optic neuropathy with ethambutol, uveitis with rifabutin, hepatotoxicity, cytopenias.
• Macrolide resistance if monotherapy or incomplete regimens are used.

Before macrolides, most patients who acquired disseminated MAC died within 3 to 4 months. With macrolides and ART, survival is greatly improved, although wasting and anaemia are common and many patients need repeated transfusion during treatment. In patients without HIV the course of pulmonary MAC is generally milder, and even extensive disease can be controlled. Relapse is common, which is why regular follow-up with sputum culture and imaging is needed during treatment. Adherence to ART predicts outcome above almost anything else. ^[1]

• Primary prevention is immune reconstitution: encourage early HIV testing and prompt ART. MAC incidence falls as the CD4 count rises, and most patients who achieve and maintain a CD4 count above 100 cells per microlitre on ART do not need prophylaxis.
• There is no vaccine and no environmental control measure that prevents exposure; the organism is ubiquitous.
• In advanced HIV, screen with blood cultures for MAC before starting primary prophylaxis, because prophylaxis must never be given when active disease is present. A compatible clinical picture (fever, weight loss, anaemia with a CD4 count under 50) warrants culture before treatment decisions are made.
• For pulmonary disease there is no screening programme; the key is to investigate chronic cough, haemoptysis and bronchiectasis properly and to obtain two sputum cultures.

Children. MAC presents mainly as cervical lymphadenitis, which runs a benign course. Prophylaxis and treatment in HIV are extrapolated from adult guidance and should follow specialist paediatric advice. Drug dosing differs by age and weight.

Pregnancy. Decisions should be made with specialist consultation; macrolides and ethambutol are generally used but the complete regimen and pregnancy interactions need individual review.

Older women. The nodular bronchiectatic form is the classic presentation. Treat early when progressive, because radiologic damage accumulates.

Immunocompromised non-HIV patients. The same antimicrobial principles apply, but the underlying cause of immunosuppression must be addressed.

Patients on biologic or post-transplant therapy. NTM infections are more common after haematopoietic stem cell transplantation than after solid organ transplantation; management is with infectious disease specialists.

The central difficulty is not the drugs but the diagnosis ^[4]. In many settings:

• MAC and tuberculosis present similarly (fever, weight loss, cough, wasting, abnormal chest imaging) and acid-fast smears cannot distinguish them. They may produce false-positive acid-fast sputum smears and lead to incorrect tuberculosis treatment.
• Microbiological culture remains the preferred method for identifying MAC but is difficult to implement in most resource-limited settings. ^[4]
• Radiology and clinical assessment help establish severity and form but not species.
• Treatment uses widely available drugs (azithromycin or clarithromycin, ethambutol, and rifampin or rifabutin). Where culture is unavailable, a patient with advanced HIV and compatible illness who fails anti-tuberculosis therapy should be reassessed and a macrolide added on specialist advice rather than assumed to have tuberculosis.

On the prevention side, the same principles apply: in advanced HIV, provide the standard package (screening, prophylaxis for major infections where appropriate, rapid ART). For MAC this means that where macrolides and blood culture are not available, rapid and effective ART remains the single most important intervention to prevent MAC disease, because prophylaxis only works in a narrow window and is not possible without basic laboratory support.

• MAC is an environmental organism, not spread person-to-person. Infection follows environmental exposure, usually inhalation.
• In advanced HIV (CD4 under 50 cells per microlitre, untreated or unsuppressed) MAC usually disseminates, producing fever, night sweats, weight loss, diarrhoea, hepatosplenomegaly and anaemia. Blood culture for mycobacteria is the key test.
• In immunocompetent people pulmonary MAC presents mainly as nodular bronchiectatic disease in older women and as fibrocavitary disease in men with chronic lung disease.
• A macrolide is the backbone of treatment. Dual therapy (macrolide plus ethambutol) or triple therapy (adding a rifamycin) for disseminated disease; a three-drug regimen for pulmonary disease, for at least 12 months after culture conversion and until CD4 recovery in HIV.
• Effective ART is started or continued with MAC treatment. It converts MAC from a fatal illness into a curable one.
• Routine primary prophylaxis is no longer recommended with prompt, effective ART. It is reserved for people with CD4 under 50 who are not on suppressive ART, after blood cultures exclude active disease.
• In low-resource settings the practical challenges are diagnosis (MAC versus TB, smear versus culture) and access to cultures; treatment drugs are widely available.

HIV infection; tuberculosis; bronchiectasis; chronic obstructive pulmonary disease; opportunistic infections in advanced HIV; non-tuberculous mycobacterial disease.